ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.279G>A (p.Met93Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004004.6(GJB2):c.279G>A (p.Met93Ile)
Variation ID: 44733 Accession: VCV000044733.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189303 (GRCh38) [ NCBI UCSC ] 13: 20763442 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Feb 14, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.279G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Met93Ile missense NC_000013.11:g.20189303C>T NC_000013.10:g.20763442C>T NG_008358.1:g.8673G>A LRG_1350:g.8673G>A LRG_1350t1:c.279G>A LRG_1350p1:p.Met93Ile P29033:p.Met93Ile - Protein change
- M93I
- Other names
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- Canonical SPDI
- NC_000013.11:20189302:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
556 | 617 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2017 | RCV000037832.14 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000523752.20 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 17, 2017 | RCV000675160.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2022 | RCV002228124.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 17, 2022 | RCV002482993.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511672.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: GJB2 c.279G>A (p.Met93Ile) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three … (more)
Variant summary: GJB2 c.279G>A (p.Met93Ile) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251190 control chromosomes. c.279G>A has been reported in the literature in individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Wu_2002, Cryns_2004, Snoeckx_2005, Tsukada_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002274257.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 93 of the GJB2 protein (p.Met93Ile). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 93 of the GJB2 protein (p.Met93Ile). This variant is present in population databases (rs397516871, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 12172394, 14985372). ClinVar contains an entry for this variant (Variation ID: 44733). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 22592158). This variant disrupts the p.Met93 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jun 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061494.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Met93Ile variant in GJB2 has been reported in at least 8 individuals with hearing loss including four compound heterozygotes with pathogenic variants in t … (more)
The p.Met93Ile variant in GJB2 has been reported in at least 8 individuals with hearing loss including four compound heterozygotes with pathogenic variants in t rans (Wu 2002, Cryns 2004, Najmabadi 2005, Snoeckx 2005, Putcha 2007, Naghavi 20 08, Rodriguez-Paris 2010, Tsukada 2010, LMM data). (Wu 2002, Cryns 2004, Tsukada 2010). The hearing loss described in these four individuals ranged from mild t o moderately-severe (Wu 2002, Cryns 2004, Tsukada 2010, LMM data). This variant has also been identified in 4/126570 European chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516871). Alth ough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency for nonsyndromic hear ing loss. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Met93Ile variant is li kely pathogenic based on compound heterozygosity in multiple affected individual s. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(Feb 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617688.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18776652, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18776652, 16380907, 14985372, 25616557, 17666888, 20497192, 20668687, 12172394, 25388846, 28483220, 25555641, 25447126, 22592158, 22695344, 30245029, 30708180, 24156272, 15666300) (less)
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Likely pathogenic
(Oct 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048130.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The GJB2 c.279G>A; p.Met93Ile variant (rs397516871) is reported in the literature in multiple individuals affected with hearing loss often found with a second pathogenic variant … (more)
The GJB2 c.279G>A; p.Met93Ile variant (rs397516871) is reported in the literature in multiple individuals affected with hearing loss often found with a second pathogenic variant (Cryns 2004, Naghavi 2008, Najmabadi 2005, Putcha 2007, Wu 2002). This variant is also reported in ClinVar (Variation ID: 44733). This variant is found in the non-Finnish European population with an allele frequency of 0.003% (3/113608 alleles) in the Genome Aggregation Database. The methionine at codon 93 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.874). Based on available information, this variant is considered to be likely pathogenic. References: Cryns K et al. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet. 2004 Mar;41(3):147-54. PMID: 14985372. Naghavi A et al. GJB2 mutations in Baluchi population. J Genet. 2008 Aug;87(2):195-7. PMID: 18776652. Najmabadi H et al. GJB2 mutations: passage through Iran. Am J Med Genet A. 2005 Mar 1;133A(2):132-7. PMID: 15666300. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. PMID: 17666888. Wu BL et al. Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002 Jul-Aug;4(4):279-88. PMID: 12172394. (less)
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Likely pathogenic
(May 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mutilating keratoderma
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Palmoplantar keratoderma-deafness syndrome Knuckle pads, deafness AND leukonychia syndrome Autosomal recessive nonsyndromic hearing loss 1A X-linked mixed hearing loss with perilymphatic gusher Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786112.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jul 17, 2017)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800777.2
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Screening of genetic alterations related to non-syndromic hearing loss using MassARRAY iPLEX® technology. | Svidnicki MC | BMC medical genetics | 2015 | PMID: 26399936 |
Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
Understanding of the molecular evolution of deafness-associated pathogenic mutations of connexin 26. | Han XH | Genetica | 2014 | PMID: 25447126 |
Optimization of simultaneous screening of the main mutations involved in non-syndromic deafness using the TaqMan® OpenArray™ Genotyping platform. | Martins FT | BMC medical genetics | 2013 | PMID: 24156272 |
Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations. | Easton JA | The Journal of investigative dermatology | 2012 | PMID: 22592158 |
Genotyping with a 198 mutation arrayed primer extension array for hereditary hearing loss: assessment of its diagnostic value for medical practice. | Rodriguez-Paris J | PloS one | 2010 | PMID: 20668687 |
A large cohort study of GJB2 mutations in Japanese hearing loss patients. | Tsukada K | Clinical genetics | 2010 | PMID: 20497192 |
GJB2 mutations in Baluchi population. | Naghavi A | Journal of genetics | 2008 | PMID: 18776652 |
A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. | Putcha GV | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17666888 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
GJB2 mutations: passage through Iran. | Najmabadi H | American journal of medical genetics. Part A | 2005 | PMID: 15666300 |
A genotype-phenotype correlation for GJB2 (connexin 26) deafness. | Cryns K | Journal of medical genetics | 2004 | PMID: 14985372 |
Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. | Wu BL | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172394 |
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Text-mined citations for rs397516871 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.